Voraxaze™ - an enzyme that breaks down methotrexate (MTX)
Voraxaze™ fact sheet
Voraxaze™ US supplies
Voraxaze™ Emergency Enquiries:
Europe/RoW:
David Briscoe Tel: +44 (0)207 246 9950 / Mob: +44 (0)7968 492 957
IDIS Customer Services:
UK & Republic of Ireland: +44 (0)1932 824100
Other EU countries:+44 (0)1932 824123
Out of hours emergency line: +44 (0)1932 824198
US:
US intravenous and US LV PK: AAIPharma: +1 866 918 1731
US intrathecal: Protherics Inc: +1 888 327 1027
Voraxaze™ (glucarpidase, previously known as carboxypeptidase G2 or CPG2) is a biological product designed to rapidly reduce the amount of blood levels of methotrexate (MTX), a commonly used cancer drug in the blood. High doses of MTX can cause kidney damage in some cancer patients and this can delay the elimination of MTX from the body. Prolonged exposure to high concentrations of MTX commonly results in serious toxic effects such as mucositis (painful mouth sores), reduced platelet and white blood counts (myelosuppression) , kidney failure and an increased risk of sepsis and in some instances death. A number of cancer patients die every year from MTX induced toxicity, mainly due to sepsis. Voraxaze™ is the only drug which can remove MTX from the blood; dialysis is the only other way to remove MTX from the blood.
Voraxaze™ is given via a simple intravenous infusion and rapidly reduces the amount of MTX in the bloodstream. Voraxaze™ contains a recombinant enzyme (glucarpidase) which rapidly cleaves MTX into a non-toxic form. In one pivotal and two supportive studies, Voraxaze™ was able to achieve a clinically important reduction (CIR) in MTX concentration to ≤1 µmol/L in the majority of patients treated. This concentration of MTX is a generally accepted threshold below which the risk of severe MTX toxicity is considered to be low. Voraxaze™ consistently reduced plasma or serum MTX concentrations by an average of >98% by the time of the first sample point, which was usually 15 minutes after Voraxaze administration in each of the three studies.
In clinical studies, a total 25/329 (8%) patients reported 50 adverse events with a possible relationship to Voraxaze™; about a third of these were considered to be allergic reactions (burning sensation, flushing, hot flush, allergic dermatitis, feeling hot, pruritis, hypersensitivity). Two of the adverse events were considered serious, hypertension and arrhythmia, but neither was definitively associated with use of Voraxaze™ and the latter was considered more likely to be associated with MTX.
Availability
As of 25 May 2007, Voraxaze™ is available for intravenous use in the US under an Open-Label Treatment Protocol and cost recovery program or the US Leucovorin PK study. The procedure for obtaining Voraxaze™ for treatment of patients with intrathecal overdose of methotrexate continues to be via an Emergency Use IND. In Canada, Voraxaze™ can be obtained via SAP through our distributer, McKessen. Voraxaze™ is also available on a named patient basis in the US and other non-US countries through our distributer IDIS Pharmaceuticals.
Development status
Voraxaze™ was granted orphan drug status in both the US and Europe in 2003.
Voraxaze™ has been granted Fast Track Designation in the US and Protherics intends to resubmit a rolling submission of the Biological License Application (BLA) starting early in the second half of 2008, after additional manufacturing and stability data has been obtained. Protherics will also undertake a small 12 patient study to support a label claim regarding the dosing of leucovorin, a rescue agent routinely given to patients receiving high doses if MTX, following administration of Voraxaze™. Protherics intends to seek a Priority Review, reducing the time for the BLA review from 10 to 6 months from submission of the final part of the application and providing a potential approval in the US in 2010.
In Europe, Protherics submitted a Marketing Authorisation Application (MAA) for Voraxaze™ to the European Medicines Evaluation Agency (EMEA) in June 2005. The EMEA subsequently requested further manufacturing and stability data, in addition to data to assess the clinical relevance of the interaction between Voraxaze™ and leucovorin. These data could not be provided in the time permitted by the Centralized Procedure and so the MAA was withdrawn in May 2007.
The manufacturing and stability data being generated to support the BLA in the US are expected to also support a MAA in the EU. Protherics will consider resubmitting a MAA application if the 12 patient study to support the label claim for leucovorin dosing requested by the FDA is deemed acceptable by the EMEA to address their concern about the clinical relevance of the leucovorin interaction. Protherics will continue supplying Voraxaze™ on a named patient basis in Europe for intervention use in patients at risk of severe or life-threatening methotrexate toxicity due to delays in their elimination of MTX following high dose MTX therapy.
Planned Use
A development programme is ongoing to expand the indications for Voraxaze™ to include planned repeated use, a market opportunity which could be worth up to US$100-200 million per annum.
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